These findings reveal that the levels of IL-23, IL-17, and IFN-gamma are elevated in BD patients with active uveitis, and they suggest that the IL-23/IL-17 pathway together with IFN-gamma is associated with the active intraocular inflammation in BD patients.

Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1-dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1-independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1-dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1-independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.retinal ischemia/reperfusion injury | cell apoptosis A cute glaucoma is a significant cause of permanent vision loss and irreversible blindness worldwide (1). It is most common among people of Asian descent, in part due to their having a more crowded anterior chamber (2, 3). With a rapid increase in intraocular pressure (IOP) to levels exceeding retinal perfusion pressure, there is resulting retinal ischemia and retinal ganglion cell (RGC) death. Individuals with angle closure glaucoma are much more likely to lose vision and become blind than those with primary open-angle glaucoma (4). The precise mechanisms by which elevated IOP leads to RGC death are not well understood. Accumulating evidence suggests that overactivated microglia have pivotal roles in triggering neurotoxicity in the CNS, including retinal inflammatory responses (5, 6), by producing proinflammatory factors such as IL-1β. IL-1β production is tightly controlled as part of the innate immune response in the CNS (7).Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are two key pattern recognition receptors (PRRs) in the initiation of the innate immune response (8-10). TLR4 has been shown to have a central role in retinal and CNS ischemia/reperfusion (I/R) injuries (11-13). Neuronal death following ischemic injury activates intense inflammation, which triggers TLR4 signaling. It has been demonstrated that ...

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BackgroundAcute glaucoma is a significantly sight-threatening cause of irreversible blindness in the world characterized by a sudden and substantial intraocular pressure (IOP) increase and subsequent retinal ganglion cell (RGC) death. This study aims to explore the role of high-mobility group box 1 (HMGB1) in an acute glaucoma mouse model.MethodsAn acute glaucoma model was induced by a rapid and substantial increase IOP to 70 mmHg for 60 min via anterior chamber punctured and affused with Balance Salt Solution in C57BL/6 mice. Retinal tissue ischemic damage and loss of RGCs were assessed at 6, 24, 48, 72 h after high IOP treatment, and at 48 h, group with or without recombinant high-mobility group box 1 (rHMGB1), the HMGB1 inhibitor, glycyrrhizic acid (GA), and by HE and immunofluorescent staining. The nuclear factor κB (NF-κB) inhibitor, JSH-23, and caspase-8 inhibitor, Z-IETD-fmk, were injected into vitreous. Reverse transcription and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunoprecipitation were performed to evaluate the expression level of nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), phosphor-NF-κB p65, caspase-8, caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), and interleukin-1β (IL-1β).ResultsHMGB1 was increased in ischemic retinal tissue during acute glaucoma as early as 6 h after rapid IOP elevation. Exogenous HMGB1 exacerbated retinal ischemic damage, RGC loss, and inhibition of endogenous HMGB1 significantly reduced the severity of disease. HMGB1 significantly induced the elevation of canonical NLRP3, ASC, caspase-1, and non-canonical capase-8-ASC inflammasome and promoted the processing of IL-1β. Furthermore, the effect of HMGB1 on NLRP3 inflammasome activation and IL-1β production was dependent on NF-κB pathway. Thus, HMGB1/caspase-8 pathway promoted the processing of IL-1β via NF-κB pathway.ConclusionThe findings of this study identified a novel signaling pathway in which HMGB1, in response to acutely elevated intraocular pressure, activated the canonical NLRP3 and non-canonical caspase-8 inflammasomes and production of IL-1β during acute glaucoma development. These results provide new insights to the understanding of the innate response that contributes to pathogenesis of acute glaucoma.

Oxidative stress has been known to be involved in pathogenesis of dry eye disease. However, few studies have comprehensively investigated the relationship between hyperosmolarity and oxidative damage in human ocular surface. This study was to explore whether and how hyperosmolarity induces oxidative stress markers in primary human corneal epithelial cells (HCECs). Primary HCECs were established from donor limbal explants. The hyperosmolarity model was made in HCECs cultured in isosmolar (312 mOsM) or hyperosmotic (350, 400, 450 mOsM) media. Production of reactive oxygen species (ROS), oxidative damage markers, oxygenases and anti-oxidative enzymes were analyzed by DCFDA kit, RT-qPCR, immunofluorescent and immunohistochemical staining and Western blotting. Compared to isosmolar medium, ROS production significantly increased at time- and osmolarity-dependent manner in HCECs exposed to media with increasing osmolarities (350–450 mOsM). Hyperosmolarity significantly induced oxidative damage markers in cell membrane with increased toxic products of lipid peroxidation, 4–hydroxynonenal (4-HNE) and malondialdehyde (MDA), and in nuclear and mitochondria DNA with increased aconitase-2 and 8-OHdG. Hyperosmotic stress also increased the mRNA expression and protein production of heme oxygenase-1 (HMOX1) and cyclooxygenase-2 (COX2), but reduced the levels of antioxidant enzymes, superoxide dismutase-1 (SOD1), and glutathione peroxidase-1 (GPX1). In conclusion, our comprehensive findings demonstrate that hyperosmolarity induces oxidative stress in HCECs by stimulating ROS production and disrupting the balance of oxygenases and antioxidant enzymes, which in turn cause cell damage with increased oxidative markers in membrane lipid peroxidation and mitochondrial DNA damage.

IMPORTANCETo our knowledge, a set of well-defined diagnostic criteria is not yet developed for the diagnosis of Vogt-Koyanagi-Harada (VKH) disease.OBJECTIVE To develop and evaluate a set of diagnostic criteria for VKH disease using data from Chinese patients. DESIGN, SETTING, AND PARTICIPANTS This case-control study reviewed medical records of patients from a tertiary referral center between October 2011 and October 2016. Data from 634 patients with VKH disease and 623 patients with non-VKH uveitis from southern China were used to develop the Diagnostic Criteria for VKH Disease (DCV). Data from an additional group of 537 patients with a definite VKH disease diagnosis and 525 patients with non-VKH uveitis from northern China were used to evaluate the diagnostic criteria. MAIN OUTCOMES AND MEASURES Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic. RESULTSOf the 1257 patients used to construct the DCV, 665 (52.9%) were male, and the mean (SD) age at disease onset was 38.6 (13.6) years. The 3-class model and 21 clinical findings were selected by latent class analysis. Variables with a high positive rate in the early-phase or late-phase VKH group or high specificity constituted essential parameters. Constellations of these essential parameters constructed the DCV. The sensitivity and NPV of the DCV were higher than those of the Revised Diagnostic Criteria for VKH Disease (RDC)

Background: Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We sought to explore the potential molecular mechanisms underlying the causal link between high IOP and glaucomatous RGCs death.Methods: A murine retinal ischemia/ reperfusion (RIR) model and an in vitro oxygen and glucose deprivation/ reoxygenation (OGDR) model were used to investigate the pathogenic mechanisms of acute glaucoma.Results: Our findings reveal a novel mechanism of microglia-induced pyroptosis-mediated RGCs death associated with glaucomatous vision loss. Genetic deletion of gasdermin D (GSDMD), the effector of pyroptosis, markedly ameliorated the RGCs death and retinal tissue damage in acute glaucoma. Moreover, GSDMD cleavage of microglial cells was dependent on caspase-8 (CASP8)-hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, the newly identified nucleotide-binding leucine-rich repeat-containing receptor (NLR) family pyrin domain-containing 12 (NLRP12) collaborated with NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) downstream of the CASP8-HIF-1α axis, to elicit pyroptotic processes and interleukin-1β (IL-1β) maturation through caspase-1 activation, facilitating pyroptosis and neuroinflammation in acute glaucoma. Interestingly, processing of IL-1β in turn magnified the CASP8-HIF-1α-NLRP12/ NLRP3/NLRC4-pyroptosis circuit to accelerate inflammatory cascades.Conclusions: These data not only indicate that the collaborative effects of NLRP12, NLRP3 and NLRC4 on pyroptosis are responsible for RGCs death, but also shed novel mechanistic insights into microglial pyroptosis, paving novel therapeutic avenues for the treatment of glaucoma-induced irreversible vision loss through simultaneously targeting of pyroptosis.

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